High-density optical tomography of cerebral blood flow and metabolism in small animals

摘要 许多临床情况，包括中风，使大脑暴露于脑血流量（CBF）不足， 维持正常的脑代谢耗氧率（CMRO 2）的要求，从而导致 脑缺血/缺氧应激和神经障碍。有效的干预措施取决于 CBF/CMRO 2改善和最终神经恢复的结果。啮齿动物（小鼠和大鼠）占95%， 研究动物然而，在啮齿动物模型中进行神经科学研究的一个主要限制是缺乏 经济实惠的无创成像技术，用于连续和纵向监测CBF和CMRO 2 变化.大型成像模式（例如，CT、PET和MRI）需要昂贵的仪器，并且很困难， 用于纵向监测。便携式、廉价的光学/超声波技术大大扩展了选择 对于连续的脑监测尽管大多数系统缺乏高时间-空间分辨率的组合， 宽视野，以及适当的大脑深层穿透深度。此外，目前没有任何 技术能够同时成像CBF、脑组织氧饱和度（StO 2）和CMRO 2。到 为了克服这些限制，肯塔基州大学（英国）的研究人员开发了一种创新的 基于CCD/CMOS的散斑对比度扩散相关断层成像（scDCT：美国专利#9861319）技术 以适应小鼠、大鼠、小猪 和人类新生儿。虽然有效，但scDCT尚未优化传播和商业化 成像性能（信噪比、时空分辨率、准确度、易用性），以及 仪器成本和便携性。Bioptics Technology LLC（BOT）与英国合作， 优化、验证和商业化一种经济实惠、便携式、易于使用的多波长scDCT（MW- scDCT）技术，用于啮齿动物CBF、StO 2和CMRO 2分布的重复纵向成像。新 方法和算法将被开发，以实现近实时，高密度，三维成像的 大脑功能MW-scDCT将使用头部模拟体模进行严格测试和优化， 已知的光学和血液动力学特性（目标1）。绝对测量的体内校准和评价 将对照标准灌注MRI和组织学检查在患有或 无中风（目标2）。最后，优化的MW-scDCT设备将被传播到几个神经科学 英国国内外的研究人员收集有关仪器适用性和用户体验的反馈。 根据这些选定的最终用户的初步反馈，我们希望确定改进和改进措施 MW-scDCT需要在继续的第二阶段研究中生产最佳产品级器件， 商业化最终用途将扩大到更大的动物模型和人类受试者。然而，在这方面， 这个第一阶段的项目将开始与啮齿动物，因为使用小动物是更容易，更经济和有效的， 使该设备商业化，从而为临床级设备的未来商业化铺平道路。

ABSTRACT Many clinical situations, including stroke, expose the brain to insufficient cerebral blood flow (CBF) that cannot maintain normal cerebral metabolic rate of oxygen consumption (CMRO2) requirements, thereby leading to cerebral ischemic/hypoxic stresses and neurological disorders. Effective interventions are dependent on the findings of CBF/CMRO2 improvement and eventually neural recovery. Rodents (mice and rats) make up 95% of research animals. However, one major limitation with neuroscience research in rodent models is lack of affordable noninvasive imaging technologies for continuous and longitudinal monitoring of CBF and CMRO2 variations. Large imaging modalities (e.g., CT, PET, and MRI) require expensive instrumentation, and are difficult to use for longitudinal monitoring. Portable, inexpensive optical/ultrasonic technologies greatly expand choices for continuous cerebral monitoring although most systems lack the combination of high tempo-spatial resolution, wide field-of-view, and proper penetration depth into deep brains. Moreover, none of currently available techniques enable simultaneous imaging of CBF, cerebral tissue oxygen saturation (StO2), and CMRO2. To overcome these limitations, researchers at University of Kentucky (UK) have developed an innovative CCD/CMOS based speckle contrast diffuse correlation tomography (scDCT: US Patent #9861319) technique to accommodate noninvasive, noncontact, fast, high-density 3D imaging of CBF distributions in mice, rats, piglets, and human neonates. While effective, scDCT has not been optimized for dissemination and commercialization in terms of imaging performance (signal-to-noise ratio, temporal-spatial resolution, accuracy, easy-to-use), and instrument cost and portability. In collaboration with UK, Bioptics Technology LLC (BOT) proposes to develop, optimize, validate, and commercialize an affordable, portable, easy-to-use, multi-wavelength scDCT (MW- scDCT) technique for repeated, longitudinal imaging of CBF, StO2, and CMRO2 distributions in rodents. New methodologies and algorithms will be developed to achieve a nearly real-time, high-density, 3D imaging of cerebral function. The MW-scDCT will be rigorously tested and optimized using head-simulating phantoms with known optical and hemodynamic properties (Aim 1). In vivo calibration and evaluation of absolute measurements with MW-scDCT will be conducted against standard perfusion MRI and histological examination in rats with or without stroke (Aim 2). Finally, optimized MW-scDCT devices will be disseminated to several neuroscience researchers inside and outside UK to collect feedback regarding instrument applicability and user experience. With preliminary feedback from these selected end-users, we expect to identify refinements and improvements needed for the MW-scDCT in a continued Phase-II study to produce an optimal product-level device for commercialization. The ultimate use will be expanded to larger animal models and human subjects. However, this Phase-I project will begin with rodents as using small animals is easier, more economical and efficient for commercializing the device, thereby paving the way for future commercialization of clinical-level devices.